Abstract
As a critical member of the Retinal Determination Gene Network (RDGN), SIX1 has been regarded as a tumor promoter in various types of cancer. However, its role in papillary thyroid carcinoma (PTC) has never been investigated. In this study, thyroid carcinoma tissue microarray staining was employed to identify the expression patterns of SIX1 and its co-activator EYA1. Papillary thyroid cancer cell lines, BCPAP, and TPC-1 cells were used to investigate the potential mechanism of SIX1 in vitro and in vivo. Flow cytometry analysis, MTT assay, the growth curve assay, colony formation assay, EdU incorporation and xenograft assay were performed to demonstrate the role of SIX1 in the malignant change of PTC cells. Western blot and Real-time PCR were used to detect the interaction among the SIX1, EYA1, and STAT3 signaling. In comparison with normal tissue, high expressions of SIX1 and EYA1 were associated with a malignant tumor. Importantly, SIX1 strongly correlated with EYA1 in thyroid carcinoma tissue microarray. Functional assays indicated SIX1 increased EYA1 expression by stabilizing EYA1 at the post-transcriptional level. Besides, SIX1 promoted the proliferation and invasion of thyroid carcinoma via activation of STAT3 signaling and its downstream targets in an EYA1-dependent manner. SIX1 can integrate with EYA1 to contribute to PTC development via activation of the classical STAT3 signaling. These data suggested targeting the abnormal activation of the SIX1/EYA1 complex may represent a novel therapeutic strategy for advanced PTC patients.
Highlights
The incidence of thyroid cancer is rapidly increasing in recent two decades, and it has become the most common endocrine malignancy worldwide [1, 2]
We explored the role of SIX1 in papillary thyroid carcinoma (PTC) through in vitro and in vivo experiments, which implicated SIX1 coordinated with EYA1 to drive neoplastic growth and invasion via activation of the classical STAT3 signaling
High expressions of SIX1 and EYA1 were associated with advanced age, lymph node metastasis and clinical stage
Summary
The incidence of thyroid cancer is rapidly increasing in recent two decades, and it has become the most common endocrine malignancy worldwide [1, 2]. Understanding the molecular basis of thyroid cancer is essential for developing effective strategies for advanced PTC patients [6]. The development of therapeutic agents that target tumor driver genes is the fundament for precision medicine [7]. The complexity in molecular subtypes of PTCs is still a challenge in exploring novel biomarker for guiding personal treatment in advanced stage [9]. Alterations of critical signaling pathways in thyroid development like MAPK and PI3K-AKT can initiate tumorigenesis and promote tumor metastasis [10]. Targeting the aberrant expression of development related genes or signaling may provide an opportunity for the molecular-based treatment of thyroid cancer
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